Potential Targeting Ph+ Acute Lymphoblastic Leukemia Stem and Progenitor Cells By Modulating the CIP2A-SET-SETBP1 -Mediated Suppression of PP2A Activity
Bibliographic record
Abstract
Abstract Tyrosine kinase inhibitors (TKIs) combined with chemotherapy significantly improved outcomes in adult Philadelphia-chromosome-positive (Ph+) B-cell Acute Lymphoblastic Leukemia (B-ALL). However, high relapse rates due to development of TKI resistance or chemotherapy-induced adverse effects remain the major therapeutic challenges. Furthermore, all TKIs are not effective against Ph+leukemia-initiating cells (LICs). The tumor suppressor protein phosphatase 2A (PP2A) is inactive in almost all solid and hematopoietic tumors. Suppression of PP2A activity correlates with poor outcome and disease progression, and largely relies on the aberrant expression of CIP2A, SET and/or SETBP1. SETBP1 was discovered as a SET-interacting protein, and recently described as mutated or overexpressed in several myeloid malignancies where it acts as an independent negative prognostic factor and as an inhibitor of PP2A, however its role in lymphoid malignancies is still unknown. Thus, we postulated that SETBP1 regulates survival and self-renewal of Ph+B-ALL LICs and progenitors through inhibition of PP2A. We reported that BCR-ABL1 kinase-dependent and -independent mechanisms induce SET-dependent PP2A inhibition in Ph+ (CMLand B-ALL) progenitors and quiescent TKI-resistant CML LICs, respectively, and that SET downregulation or pharmacologic (i.e. SET-interacting PP2A-activating drugs; PADs) restoration of PP2A activity strongly impaired malignant but not normal hematopoiesis by selectively killing Ph+progenitors (CML and ALL) and TKI-resistant quiescent stem (CML) cells. Here, we show that wild type SETBP1 is markedly induced in an imatinib (IM)-insensitive manner in primary CD34+CD19+ Ph+ B-ALL progenitors and Ph+ B-ALL cell lines (BV173 and SUP-B15) and barely detectable in CD34+ cells from CML patients in chronic and blastic phase. Overexpression of SETBP1 was found essential for PP2A inhibition in Ph+ B-ALL blasts. Accordingly, shRNA-dependent SETBP1 downregulation impaired clonogenic potential and self-renewal of CD34+CD19+ Ph+ B-ALL cells in CFC and serial replating assays. Furthermore, we have evidence that a SETBP1-SET/CIP2A inhibitory complex may exist in Ph+ cells, suggesting that SETBP1 might serve to recruit SET and CIP2A to suppress PP2A activity. Indeed, we found that CIP2A, like SET and SETBP1, is also overexpressed in CD34+CD19+ Ph+ B-ALL compared to CD34+CD19+cell from BM of healthy donors. Because, SETBP1 stabilizes SET and augments PP2A inhibition, and ectopic SETBP1 expression confers self-renewal to mouse myeloid progenitors and cooperates with BCR-ABL1 to induce a CML blast crisis-like disease in mice, our data suggest that aberrant SETBP1 expression might significantly contributes to the development of Ph+ B-ALL and persistence of TKI-resistant Ph+ B-ALL LICs. Disclosures Milojkovic: Ariad: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Roy:Paladin: Consultancy; Fate Therapeutics: Consultancy; Novartis: Consultancy; Kiadis Pharma: Research Funding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".